Polymers and polymerization processes

ABSTRACT

Emulsion polymerizations are described in which the monomers include an ethylenically unsaturated ammonium phosphate ester monomer. The processes may be conducted with high total solids, to produce a polymer latex having a solids content in the range 20 to 60%, for instance in the range 25 to 50% by weight. Preferably comonomers include lower alkyl and higher alkyl methacrylate selected to give desirable glass transition temperatures and coalescing films, zwitterionic comonomers, polyethoxylated comonomers to confer desired biocompatibility and latex stability as well as good wetting for a film formed of the polymer and may contain crosslinking monomers, reactive monomers, anionic monomers and/or cationic monomers. The latexes are stable, even when the process is carried out in the substantial absence of non-polymerisable emmulsifier. Coatings formed from the latexes containing zwitterionic comonomer have good biocompatibilising properties.

The present invention relates to polymers formed from radicalpolymerization of ethylenically unsaturated monomers including anammonium phosphate ester zwitterionic monomer, and processes forproducing them. In particular, the invention relates to emulsionpolymerization processes for forming high solids emulsions without theincorporation of non-polymerisable emulsifier, and to the use of theseemulsions to biocompatibilise substrates.

Yamaguchi et al in Makromol. Chem. (1989), 190, 1195-1205, describe anoil-in-water emulsion polymerization of styrene in the presence ofpolymerisable and non-polymerisable phosphoryl choline compounds asemulsifier. The latex product is stable, the non-polymerisableemulsifiers giving more regular shaped and sized spherical particlesthan the polymerisable emulsifiers. The polymerizations were conductedto form latexes having around 10 wt % solids. The mole percent ofpolymerisable emulsifier based on total monomer is around 10%. The basemonomer on which the polymerizations were based was styrene.

Sugiyama et al in Polym. J. (1993) 25(5), 521-527, describe anemulsifier free radical polymerization of ethylenically unsaturatedmonomers comprising methylmethacrylate, in the presence of anethylenically unsaturated ammonium phosphate ester zwitterionic monomer,using a water-soluble initiator. The latex product had a concentrationof around 10% by weight polymer. Increasing the amount of zwitterionicmonomer resulted in reduced stability of the latex. Whilst low levels ofzwitterionic monomer reduced the particle size of microspheres in thelatex product as compared to a process containing no such monomer,increasing the level from a mole % of 0.01, based on total monomer, to0.5 resulted in an increase in the diameter of the microsphere of theproduct. The microspheres themselves were found to have low levels ofadsorption of albumin as compared to polymethylmethacrylate polymerisedin the absence of the ammonium phosphate ester zwitterionic monomer.

Sugiyama et al, in J. Polym. Sci., Part A (1997) 35, 3349-3357, describeoil-in-water emulsion polymerization of methylmethacrylate, optionallywith a comonomer of hydroxypropyl methacrylamide, in the presence of2-methacryloyloxyethyl-2′-trimethylammoniumethyl phosphate inner salt(MPC). The MPC is present at a level of about 1% based on totalethylenically unsaturated monomer. The latex product had a polymersolids concentration of around 10% by weight. Again the presence of MPCresulted in a decrease in the stability of the latex product with moreaggregates being formed. The process was dependent on the choice ofinitiator, between potassium peroxodisulphate, and2,2′-azobis[2-(imidazolin-2-yl)propane]dihydrochloride (ABIP). The ABIPinitiated products were more influenced by the presence of the MPCmonomer in terms of particle size and level of aggregates. In bothSugiyama papers, the reaction mixture was agitated at high speed, withall monomers being included in the reaction vessel at the commencementof the polymerization. It is not clear how the methylmethacrylatedispersed phase is maintained in suspension during the process forexample with no MPC monomer.

Zimehl et al, in Colloid Polym. Sci. (1990) 268, 924-933 describeemulsion polymerization of polystyrene using potassium peroxodisulphatein the presence of N-(3-sulphopropyl)-N-methacrylomidyl propyl(N,N-dimethylammonium betaine) (SPP) at SPP concentrations in the range5 to 70% by weight based on total monomer. The particle size of thelatex product was dependent upon the initiator and the level of betainecomonomer. Again, all of the monomers were dispersed into the aqueouscontinuous phase before polymerization was initiated. The solidsconcentration of product latex was around 10% by weight.

In U.S. Pat. No. 3,497,482 Hwa et al describe a copolymerization ofN,N-dimethyl-N-(2-methacryloyloxyethyl)-N-(3-sulphopropyl ammonium innersalt) (SPE), with ethyl methacrylate and acrylamide, in an aqueouscontinuous phase. Hwa produces a metastable oil-in-water product. Hedoes not describe the particle size of the latex.

In WO-A-93/01221 we describe a range of copolymers of zwitterionicmonomer with comonomers such as hydrophobic comonomers, ionic comonomersor reactive comonomers. The copolymers are formed by co-dissolving allthe monomers into a solvent in which monomers and polymer are solubleand recovered by precipitation techniques. It is suggested that theproduct might be a micro emulsion but no examples of emulsionpolymerization are given. The polymers are used to coat substrates inorder to improve their biocompatibility. Whilst improvements inbiocompatibility may be achieved by using molar percentages of 1% orlower of zwitterionic monomer, based on total ethylenically unsaturatedmonomer, it is often found that at least 20 mol % zwitterionic monomeris needed for satisfactory levels of improved biocompatibility. Thehigher the level of zwitterionic monomers, the greater the expense.

Zwitterionic polymers made by the techniques such as are described inWO-A-93/01221, may be blended with physically or mechanically desirablecopolymers to provide blends which have good biocompatibilisingproperties. The level of zwitterionic monomer in the total blend isreduced, thereby rendering the product more cost effective than singlecomponent zwitterionic polymer products. Such blends are described in,for instance, WO-A1-94/14897 and PCT/GB00103985 (unpublished at thepriority date of this application). PCT/GB00/03985 describes blends ofMPG copolymers with higher alkyl methacrylate comonomers, blended withalkyl(meth)acrylate polymers. Such blends, co-dissolved in a suitableorganic solvent may be coated onto a surface to form a coating havingmicro-domains of relatively hydrophilic and relatively hydrophobiccharacter. The blends may express higher levels of phosphorylcholinegroups at the surface than in the bulk of the coating. This should allowthe properties of a substrate coated with the polymer to be tailored forparticular biocompatibility.

It would be desirable to produce a latex having high solids, in which azwitterionic monomer is one of the ethylenically unsaturated monomers.It would furthermore be desirable to produce a copolymer of an ammoniumphosphate ester zwitterionic monomer including low levels of thatmonomer. It would be desirable to carry out an emulsion polymerizationto produce a stable latex product having a small particle size, and lowparticle size distribution and which forms coatings having desirablebiocompatibilising properties without using high levels of ammoniumphosphate ester zwitterionic monomer.

In a new emulsion polymerization process according to the invention, amixture of ethylenically unsaturated monomers including water-insolublemonomers is polymerised in the dispersed phase of an oil-in-wateremulsion in the presence of a water-soluble radical initiator,ethylenically unsaturated monomers including an ammonium phosphate esterzwitterionic monomer the process being characterised by being carriedout at component concentrations to give a latex product having a polymersolids concentration of at least 20% by weight.

In the new process, the solids concentration of the product is usuallyno more than 60%, preferably in the range 25 to 50% by weight.

The process of the invention may be carried out in the presence ofnon-polymerisable emulsifiers and/or stabilisers. It is found that it ispossible for the emulsion and latex product to be adequately stabilisedby the presence of the ammonium phosphate ester zwitterionic monomer,optionally in combination with other surface active monomers. Theprocess is preferably carried out therefore in the substantial absenceof non-polymerisable surfactant/emulsifier and stabiliser.

The ammonium phosphate ester zwitterionic monomer is preferably includedin an amount in the range 0.01 to 5% by weight, based on the totalweight of monomers. More preferably the level of the zwitterionicmonomer is in the range 0.05 to 2% by weight, for instance 0.1 to 1% byweight.

The zwitterionic monomer preferably has the general formula I

YBX   I

in which

X is the ammonium phosphate ester zwitterionic group;

B is a bond, or a straight branched alkanediyl, alkylene oxaalkylene, oralkylene (oligooxalkylene) group, optionally containing one or morefluorine substituents; and

Y is an ethylenically unsaturated group selected from H₂C═CR—CO—A—,H₂C═CR—C₆H₄—A¹—, H₂C═CR—CH₂A²—, R²O—CO—CR═CR—CO—O—, RCH═CH—CO—O—,RCH═C(COOR²)CH₂—CO—O—,

A is —O— or NR¹;

A¹ is selected from a bond, (CH₂)_(n)A² and (CH₂)_(n)SO₃— in which n is1 to 12;

A² is selected from a bond, —O—, O—CO—, —CO—O, —CO—NR¹—, —NR¹—CO,—O—CO—NR¹—, and —NR¹—CO—O—;

R is hydrogen or C₁₋₄ alkyl;

R¹ is hydrogen, C₁₋₄ alkyl or BX; and

R² is hydrogen or C₁₋₄ alkyl.

Generally in the zwitterionic group X, the anion is closer to B than thecation. However in some zwitterions, the cation is closer to the group Bthan is the anion (called hereinafter phosphobetaines).

Preferably X is a group of the general formula II

in which R³ is alkanediyl of 1 or more, preferably 2-6 carbon atomsoptionally containing one or more ethylenically unsaturated double ortriple bonds, disubstituted-aryl (arylene), alkylene arylene, arylenealkylene, or alkylene aryl alkylene, cycloalkanediyl, alkylenecycloalkyl, cycloalkyl alkylene or alkylene cycloalkyl alkylene, andoptionally contains one or more fluorine substituents and/or one or morefunctional groups; and

either the groups R⁴ are the same or different and each is hydrogen oralkyl of 1 to 4 carbon atoms, preferably methyl, or aryl, such asphenyl, or two of the groups R⁴ together with the nitrogen atom to whichthey are attached form an aliphatic heterocyclic ring containing from 5to 7 atoms, or the three groups R⁴ together with the nitrogen atom towhich they are attached form a fused ring structure containing from 5 to7 atoms in each ring, and optionally one or more of the groups R⁴ issubstituted by a hydrophilic functional group.

Alternatively X may be a group of the general formula III

in which the group R⁵ are the same or different and each is hydrogen,C₁₋₄ alkyl, such as methyl, or aryl, such as phenyl;

R⁶ alkanediyl of 1 or more, preferably 2-6 carbon atoms optionallycontaining one or more ethylenically unsaturated double or triple bonds,disubstituted-aryl (arylene), alkylene arylene, arylene alkylene, oralkylene aryl alkylene, cycloalkanediyl, alkylene cycloalkyl, cycloalkylalkylene or alkylene cycloalkyl alkylene, optionally contains one ormore fluorine substituents and/or one or more functional groups;

R⁷ is hydrogen, or an optionally substituted C₁₋₁₈ alkyl, C₂₋₁₈ alkenyl,C₂₋₁₈ alkynyl, C₆₋₂₄ aryl or C₇₋₂₄ aralkyl group.

In a group of the general formula III, R⁷ is preferably other thanhydrogen and is more preferably an unsubstituted C₁₋₆ alkyl, C₆₋₁₂ arylor C₇₋₁₂ aralkyl group. Any substituents in a substituted group R⁷ areusually fluorine atoms, or hydroxyl or C₁₋₄ alkoxy groups.

In the new emulsion polymerization process the monomers preferablyinclude at least 50% by weight of ethylenically unsaturatedpolymerisable monomers. Examples of suitable monomers are compoundsselected from the group consisting of C₁₋₁₂-alkyl(alk)acrylates,C₂₋₁₂-alkyl- and -dialkyl-(alk)acrylamides, water insoluble vinyl estersor ethers, allylic compounds, maleic or fumaric esters or imides,aconitic compounds, styrenic compounds, e.g. styrene, and mixturesthereof.

As is known in emulsion polymerization techniques, the choice ofmonomers affects the physical properties of the mixture, in particularwhether the polymer particles of the product are able to coalesce afterremoval of water, for instance to form stable film coatings. It ispreferred that the hydrophobic compounds are selected for their abilityto form films at suitable temperatures for coating processes.

It is found that particularly desirable characteristics are achieved byusing a blend of hydrophobic compounds, which would tend to conferdifferent properties of hardness on the resultant polymer. Monomerswhich tend to produce hard polymers are lower alkyl(meth)acrylateespecially methylmethacrylate. Compounds which tend to produce softercopolymers are alkylacrylates and methacrylates having straight orbranched alkyl groups with at least 4 carbon atoms, such as butyl,hexyl, 2-ethylhexyl or n-octyl groups. Preferably the hydrophobiccompound comprises a mixture of methylmethacrylate with a C₄₋₈ alkylacrylate.

The emulsion polymerization itself and the properties of the product,especially the biocompatibility of films produced from the emulsion, arebeneficially affected by incorporating a zwitterionic comonomer. Thezwitterionic comonomer preferably comprises as cation a quaternaryammonium or phosphonium group but may comprise a tertiary sulphoniumgroup. The anion may be a sulphonate, sulphate, phosphonate, orcarboxylate anion, most preferably a sulphonate or carboxylate anion.Most preferably the comonomer is a sulpho- or carboxy-betaine monomer.The zwitterionic comonomer is suitably a compound of the general formulaIV

Y¹B¹X¹   IV

in which

Y¹ is an ethylenically unsaturated group selected from H₂C═CR⁸—CO—A⁶—,H₂C═CR⁸—C₆H₄—A³—, H₂C═CR⁸—CH₂A⁴—, R⁹O—CO—CR⁸═CR⁸—CO—O—, R⁸CH═CH—CO—O—,R⁸CH═C(COOR⁹)CH₂—CO—O,

A⁶ is —O— or NR¹⁰;

A³ is selected from a bond, (CH₂)_(m)A⁴ and (CH₂)_(m)SO₃— in which m is1 to 12;

A⁴ is selected from a bond, —O—, O—CO—, CO—O, —CO—NR¹⁰—, —NR¹⁰—CO,—O—CO—NR¹⁰—, and NR¹⁰—CO—O—;

R⁸ is hydrogen or C₁₋₄ alkyl;

R¹⁰ is hydrogen, C₁₋₄-alkyl or B¹X¹;

R⁹ is hydrogen or C₁₋₄ alkyl;

B¹ is a bond, or a straight branched alkanediyl, alkylene oxaalkylene,or alkylene (oligooxalkylene) group, optionally containing one or morefluorine substituents; and

X¹ is a zwitterionic group other than an ammonium phosphate ester.

The zwitterionic group X¹ may have, as anion a carboxylate group, asulphate group, a sulphonate group or a phosphonate group, preferablycarboxylate or, more preferably a sulphonate group. The zwitterionicgroup X¹ may have as cationic group an ammonium, phosphonium orsulphonium group, preferably an ammonium group.

A preferred zwitterionic group X¹ has the general formula V

where the groups R¹¹ are the same or different and each is hydrogen orC₁₋₄ alkyl and s is from 2 to 4. Preferably the groups R¹¹ are the same.It is also preferable that at least one of the groups R¹¹ is methyl, andmore preferable that the groups R¹¹ are both methyl. Preferably s is 2or 3, more preferably 3.

Alternatively the zwitterionic group may be an amino acid moiety inwhich the alpha carbon atom (to which an amine group and the carboxylicacid group are attached) is joined through a linker group to thebackbone of the biocompatible polymer. Such groups may be represented bythe general formula VI

in which

A⁵ is a valence bond, —O—, —S—or —NH—, preferably —O—,

R¹² is a valence bond (optionally together with A⁵) or alkanediyl,—C(O)alkylene-, NHCOalkylene or —C(O)NHalkylene, preferably alkanediyland preferably containing from 1 to 6 carbon atoms; and

the groups R¹³ are the same or different and each is hydrogen or alkylof 1 to 4 carbon atoms, preferably methyl, or two or three of the groupsR¹³, together with the nitrogen to which they are attached, form aheterocyclic ring of from 5 to 7 atoms, or the three group R¹³ togetherwith the nitrogen atom to which they are attached form a fused ringheterocyclic structure containing from 5 to 7 atoms in each ring.

Alternatively the zwitterion may be a carboxy betaine—N^(⊕)(R¹⁴)₂(CH₂)_(r)COO^(⊖) in which the R¹⁴ groups are the same ordifferent and each is hydrogen or C₁₄ alkyl and r is 2 to 6, preferably2 or 3.

In another embodiment, the zwitterionic group X¹ has the general formulaVII

W is S, PR¹⁶ or NR¹⁶;

the or each groups R¹⁶ is hydrogen or alkyl of 1 to 4 carbon atoms orthe two groups R¹⁶ together with the heteroatom to which they areattached form a heterocyclic ring of 5 to 7 atoms;

R¹⁷ is alkanediyl of 1 to 20, preferably 1 to 10, more preferably 1 to 6carbon atoms;

A⁷ is a bond, NH, S or O, preferably O; and

R¹⁸ is a C₁₋₁₂ alkyl, C₇₋₁₈ aralkyl or C₆₋₁₈ aryl group or, where A⁷ isother than a bond, is a C₁₋₁₂-alkoxy, C₆₋₁₈-aryloxy or C₇₋₁₈-aralkoxygroup.

In compounds comprising a group of the general formula VII, it ispreferred that

W is NR¹⁶;

each R¹⁶ is C₁₋₄ alkyl; and

R¹⁷ is C₂₋₆ alkanediyl.

In all embodiments, in the zwitterionic comonomer of the general formulaIV Y¹ is preferably H₂C═CR⁸—CO—A³ —. Such acrylic moieties arepreferably methacrylic, that is in which R⁸ is methyl, or acrylic, inwhich R⁸ is hydrogen. Whilst the compounds may be acrylamido compounds(in which A is NR¹⁰), in which case R¹⁰ is preferably hydrogen, or lesspreferably, methyl, most preferably the compounds are esters, that is inwhich A³ is O. Suitable examples of comonomer of the general formula IVare SPP and SPE.

In monomers of the general formula IV, especially where Y is thepreferred acrylic group, B¹ is most preferably an alkanediyl group.Whilst some of the hydrogen atoms of such group may be substituted byfluorine atoms, preferably B¹ is an unsubstituted alkanediyl group, mostpreferably a straight chain group having 2 to 6 carbon atoms.

Where a zwitterionic comonomer is included, the ratio of that comonomerto ammonium phosphate ester zwitterionic monomer is preferably in therange (1 to 50):1, more preferably in the range (5 to 20):1.

The ethylenically unsaturated monomers may further comprise hydrophilicmonomer, for instance relatively water-soluble monomers.

Hydrophilic monomers are preferably selected from the group consistingof C₁₋₄-hydroxyalkyl(meth)acrylates, C₁₋₄-hydroxyalkyl(meth)acrylamides,C₁₋₃-alkoxy-C₂₋₄-alkyl(meth)acrylates,C₁₋₃-alkoxy-C₂₋₄-alkyl(meth)acrylamides,C₁₋₃-alkoxy-oligoethoxy(meth)acrylates,C₁₋₄-dihydroxyalkyl(meth)acrylates, N-mono- or N,N- di- C₁₋₂ alkyl(meth)acrylamides, N-vinylactams, andC₂₋₄-hydroxyalkyl-oligoethoxy(meth)acrylates and mixtures thereof.

It has been found to be particularly useful to include, as a hydrophilicmonomer, a monomer comprising an oligoethoxy moiety, that is selectedfrom C₁₋₃-alkoxy-oligoethoxy(meth)acrylates andC₂₋₄-hydroxyalkyl-oligoethoxy(meth)acrylates, more preferably the alkoxyterminated compounds. Preferably an alkoxy group is methoxy or ethoxy.Such compounds preferably have 5 to 50 ethoxy groups, for instance inthe range 10 to 20 methoxy groups. Oligoethoxylated polymerisablecompounds improve the stability of the emulsion during the process, aswell as the latex product, and may confer desirable wettingcharacteristics on a product polymer as well as useful biocompatibility.

A hydrophilic monomer is preferably included in an amount in the range0.1 to 50% by weight of total monomers, more preferably an amount in therange 1 to 25% by weight, for instance an amount in the range 5 to 20%by weight. An oligo ethoxylated comonomer is preferably included in anamount in the range 1 to 20% by weight, more preferably in the range 5to 10% by weight. It is often used in conjunction with one or more otherhydrophilic monomers, such that the total amount of hydrophilic monomeris in the range 5 to 50% by weight.

The stability of the emulsion during polymerization is found to beimproved if the pH of the emulsion is maintained slightly acidic, thatis has a pH less than 7, more preferably in the range 4 to 6.8, forinstance about 5. Whilst the acidity may be achieved by adding anon-polymerisable acid for instance a mineral acid, to the emulsion, itis preferable to include a polymerisable acid as one of theethylenically unsaturated monomers. Preferably an ethylenicallyunsaturated acid is selected from fumaric acid, maleic acid, vinylsulphonic acid and styrene sulphonic acid, more preferably selected fromacrylic and methacrylic acids, and is most preferably methacrylic acid.

Where acidic monomer is included, it is present in an amount in therange 0.1 to 5% by weight, more preferably in the range 0.2 to 2% byweight, based on the total weight of monomers.

Other compounds, especially other monomers may be included in thepolymerization mixture, for instance to achieve desired productcharacteristics.

It may also be desirable to include non-polymerisable components in thepolymerization mixture, for instance in the continuous aqueous phase orin the dispersed oil phase, or at the interface. Non-polymerisableemulsifiers and suspending agents may be included, but are preferablynot included. Drugs, especially water-insoluble, oil-soluble drugs maybe added whereby they may become absorbed in the latex particles of theproduct.

It may be desirable to include cationic monomer, in order to provide aproduct polymer having an overall cationic charge.

As described in our application number WO-A-93/01221 and WO-A-98/22516,the presence of cationic groups in a polymer may confer desirablebinding properties either to underlying counterionically chargedsurfaces, or to anionic compounds which may be contacted with a surfacecoated with the polymer to achieve desirable results.

A cationic monomer is preferably a compound of the general formula VIII

Y²B²Q   VIII

in which

Y² is an ethylenically unsaturated group selected from H₂C═CR¹⁹—CO—A⁸—,H₂C═CR¹⁹—C₆H₄—A⁹—, H₂C═CR¹⁹—CH₂A¹⁰, R²¹O—CO—CR¹⁹═CR¹⁹—CO—O—,R¹⁹CH═CH—CO—O—, R¹⁹CH═C(COOR²¹)CH₂—CO—O—,

A⁸ is —O— or —NR²⁰—;

A⁹ is selected from a bond, (CH₂)_(q)A¹⁰ and (CH₂)_(q)SO₃— in which q is1 to 12;

A¹⁰ is selected from a bond, —O—, O—CO—, —CO—O, —CO—NR²⁰—, —NR²⁰—CO,O—CO—NR²⁰—, and NR²⁰—CO—O—;

R¹⁹ is hydrogen or C₁₋₄ alkyl;

R²⁰ is hydrogen, C₁₋₄ alkyl or BX.

R²¹ is hydrogen or C₁₋₄ alkyl;

B² is a bond, or a straight branched alkanediyl, alkylene oxaalkylene,or alkylene (oligooxalkylene) group, optionally containing one or morefluorine substituents; and

Q is —N^(⊕)R²² ₃, —P^(⊕)R²³ ₃ or —S^(⊕)R₂₃ ₂ in which either the groupsR²² are the same or different and each is hydrogen, alkyl of 1 to 6carbon atoms, preferably methyl, C₁₋₆ hydroxyalkyl, aryl, such asphenyl, or C₇₋₁₂ aralkyl, or two of the groups R²² together with thenitrogen atom to which they are attached form an aliphatic heterocyclicring containing from 5 to 7 atoms, or the three groups R²² together withthe nitrogen atom to which they are attached form a fused ring structurecontaining from 5 to 7 atoms in each ring, and optionally one or more ofthe groups R³ is substituted by a hydrophilic functional group, and

the groups R²³ are the same or different and each is R²² or a groupOR²², where R²² is as defined above mutatis mutandis.

In the cationic monomer of the general formula VIII Q is preferably—N^(⊕)R²² ₃, in which each R²² is a C₁₋₄ alkyl group, preferably eachR²² being methyl. The group Y² is preferably an acrylic group, that isof the formula H₂C═CR¹⁹COA⁸. In such groups R¹⁹ is either hydrogen ormethyl, preferably methyl, and A⁸ is preferably —O—. B² is preferably aC₂₋₆₁₈ alkanediyl group, more preferably a C₂₋₆ alkanediyl. Examples ofsuitable cationic monomers are 2-(N,N-dimethylamino)ethyl methacrylatemethyl chloride or methyl sulphate salt, and 2-(N,N-dimethyl amino)ethyl acrylate methyl chloride or methyl sulphate salt.

A cationic monomer may be included in an amount in the range 0.1 to 25%by weight, more preferably an amount in the range 1 to 20% by weight,most preferably in an amount in the range 2 to 15% by weight.

Other monomers which may useful be included in the mixture includefunctional monomers, comprising reactive groups which are useful toprovide attachment points for ligands or for underlying substratesurfaces having co-reactive functional groups, or to provide inter- orintra-molecular crosslinkability. Such functional groups may react withco-reactive groups derived from other functional monomers such ashydroxyl or amine group containing monomers.

Preferably a reactive monomer has the general formula IX

Y³B³Q¹   IX

in which

Y³ is an ethylenically unsaturated group selected from H₂C═CR²⁴—CO—A¹¹—,H₂C═CR²⁴—C₆H₄—A¹², H₂C═CR¹⁹—CH₂A¹³, R²⁶O—CO—CR²⁴═CR—CO—O—,R²⁴CH═CH—CO—O—, R²⁴CH═C(COOR²⁶)CH₂—CO—O—,

A¹¹ is —O— or —NR²⁵;

A¹² is selected from a bond, (CH₂)_(r)A¹³ and (CH₂)_(r)SO₃— in which ris 1 to 12;

A¹³ is selected from a bond, —O—, O—CO—, CO—O, —CO—NR²⁵—, —NR²⁵—CO,—O—CO—NR²⁵, and NR²⁵—CO—O—;

R²⁴ is hydrogen or C₁₋₄ alkyl;

R²⁵ is hydrogen, C₁₋₄-alkyl or B³Q¹;

R²⁶ is hydrogen or C₁₋₄ alkyl;

B³ is a bond, or a straight branched alkanediyl, alkylene oxaalkylene,or alkylene (oligooxalkylene) group, optionally containing one or morefluorine substituents.

Q¹ is a reactive group selected from the group consisting of aldehydegroups; silane and siloxane groups containing one or more substituentsselected from halogen atoms and C₁₋₄-alkoxy groups; hydroxyl; amino;carboxyl; epoxy; —CHOHCH₂Hal (in which Hal is selected from chlorine,bromine and iodine atoms); succinimido; tosylate; triflate; imidazolecarbonyl amino; optionally substituted triazine groups; cinnamyl;ethylenically and acetylenically unsaturated groups; acetoacetoxy;methylol; and chloroalkylsulphone groups; acetoxy; mesylate; carbonyldi(cycloalkyl carbodiimidoyl; and oximino.

Preferred groups Q¹ are aldehyde, reactive silane and siloxane, amino,epoxy, CHOHCH₂Hal (in which Hal is halogen), succimimido, tosylate,triflate, imidazolecarbonyl amino and optionally substituted triazinegroups. Most preferably Q¹ is a trialkoxy silyl group, such as atrimethoxysilyl group.

In the reactive monomer of the general formula IX the ethylenicallyunsaturated group Y³ is preferably and acrylic type group, that is agroup H₂C═CR²⁴A¹¹—, R²⁴ preferably being hydrogen or, most preferably,methyl and A¹¹ preferably being —O—. Preferred groups B³ are C₂₋₁₈alkanediyl, most preferably C₂₋₆-alkanediyl.

The emulsion polymerization of the invention may be carried out in asingle step, in which all of the monomers are dispersed into an aqueouscontinuous phase and agitation applied to form an emulsion havingsuitable sized droplets followed by initiation of polymerization.However, optimum particle size distribution is achieved if a two-stepprocess is used, in a first step of which a seed polymer is formed, andin the second step the seeds are grown. In such a process, the seedmonomers are dispersed into the aqueous phase and polymerization isinitiated. To the seed polymer latex, the remaining monomers andadditional initiator are added, so that polymerization is initiated atthe seeds. Monomer travels from monomer droplets to the polymer seeds.

Preferably in a process involving a seed polymerization step, themonomers from which the seed polymer is formed comprise at least aportion of the ammonium phosphate ester zwitterionic monomer which ispreferably added to the polymerization mixture in the form of an aqueoussolution. The seed monomers must include at least a portion of thewater-insoluble monomers. These monomers are dispersed into the aqueouscontinuous phase in the presence of the ammonium phosphate esterzwitterionic monomer whereby an emulsion of seed monomer is formed.Polymerization is initiated by radical initiator by a water-solubleinitiator.

After seed polymerization has continued until the yield of polymer is atleast 1% based on solids, seed growth emulsion polymerization step isthen carried out by adding further monomer including at least a portionof the remaining water-insoluble monomer to the emulsion, along withfurther water-soluble initiator. It may be desirable for the polymerformed after the initial seed polymerization step to have asubstantially constant composition. In this case, it is desirable for awater-immiscible liquid containing the water-insoluble monomers andother compatible comonomers and for this mixture to be added in a singleaddition step or continuously over an extended period to the aqueousreaction mixture. If any of the monomers selected components for theethylenically unsaturated monomers are immiscible with thewater-insoluble monomer blend, it may be desirable for the or all of themonomers of that type to be added separately to the polymerizationmixture, for instance in the form of an aqueous solution.

It is preferred that the monomer blend be added over a period duringwhich polymerization continues to the reaction mixture, and thatpolymerization be continued after all of the monomer has been added.During the monomer feed period, it is preferred for initiator to becontinuously added to the reaction mixture. Preferably a portion ofinitiator is retained until after all of the monomer has been added tothe mixture and is then included to minimise the level of residualunpolymerised monomer in the product.

It may be desirable for the polymerization to form a core-shellmorphology. Such morphologies are generally achieved by carrying out thepolymerization, generally after a seed polymerization step, in two ormore phases. Generally the polymer formed in the two or more phasesdiffers in terms of the monomers used and/or their ratios. Using suchtechniques it is possible to form a product latex in which the polymerparticles have tailored characteristics with cores and shells of desiredhardness, desired hydrophilicity or desired porosity. Suchcharacteristics are achieved by selecting monomers according to theirglass transition temperatures, hydrophilicities, or crosslinkability. Toachieve a low porosity product, for instance, it may be desirable toincorporate di-, tri- or higher-functional ethylenically unsaturatedmonomers, or to include functional monomers which may be reacted withthe same or different functional monomers during or after polymerizationto provide intermolecular crosslinks.

Core/shell morphology may be achieved by changing the composition ofmonomers added to the polymerization mixture during the polymerizationprocess. Thus monomers for forming the core should be added andpolymerised in the mixture before addition of monomers for forming theshell.

In one particular embodiment of the process of the invention, azwitterionic comonomer is included as part of the ethylenicallyunsaturated monomer and is added to the polymerization mixture as acomponent of the aqueous initiator composition, and is preferably addedcontinuously over a monomer feed period during which water-insolublemonomer blend is separately added to the polymerization mixture.Preferably a monomer feed period is conducted for a period in the range5 to 1200 minutes, most preferably in the range 30 to 240 minutes.

By the use of the ammonium phosphate ester zwitterionic monomer it hasbeen found possible to conduct the emulsion polymerization underconditions such that high solid content latex products are formed. Thusthe level of polymer in the latex product may be higher than 20% byweight, for instance up to 6%, preferably in the range 20 to 60% byweight, without adversely affecting the stability nor viscosity. Suchlatexes are convenient to handle. Whilst water may be evaporated fromthe product latex to achieve such high solids materials, or the polymerparticles may be recovered by agglomeration or coagulation techniquesand redissolved into water, preferably no such steps are carried out toachieve the 20 to 50% by weight solids latex. Alternatively the latexmay be diluted before use or compounded with other ingredientscompatible with its end use, such as water, other latices or coalescingaids. Coalescing aids may assist in the film formation of the finalproduct, especially where the polymer is film forming at a highertemperature than room temperature. One suitable component is a latexpreservative, for instance which inhibits bacterial growth or is abiocide or fungicide, suitably an alcohol such as benzyl alcohol.

It is believed that this is the first time that ammonium phosphate esterzwitterionic monomers have been used in emulsion polymerizationprocesses including a seed polymer formation phase. According to afurther aspect of the invention there is provided a seeded emulsionpolymerization process in which a mixture of ethylenically unsaturatedmonomers including water-insoluble monomers and an ammonium phosphateester zwitterionic monomer is copolymerised in the dispersed phase of anoil-in-water emulsion in the presence of a water-soluble radicalinitiator comprising the steps

i) providing an aqueous solution comprising at least a portion of theammonium phosphate ester zwitterionic monomer and a portion of theinitiator;

ii) forming a dispersed phase comprising a monomer seed compositioncomprising at least a portion of the water-insoluble monomers to form aseed emulsion;

iii) initiating polymerization of the seed emulsion whereby a seed latexis formed;

iv) providing a seed growth monomer mixture comprising the remainingwater-insoluble monomers; and

v) adding the monomer cell mixture to the seed polymer latex andinitiating polymerization of the monomers of the seed growth mixture inthe dispersed seeds, to form a product polymer latex.

In the seeded emulsion polymerization process it is preferred that allof the ammonium phosphate ester zwitterionic monomer is present in theseed polymerization mixture.

Whilst the novel seeded polymerization process may be carried out toprovide a relatively low solid product polymer latex of less than 20%,for instance in the range 2 to 20%, it is possible to carry out theprocess under conditions such that the product latex has a solidconcentration in the range 20 to 60% by weight.

The seeded polymerization process allows formation of a product polymerlatex having very low distribution of product particle size. Theparticle size may be controlled by the levels of seed monomer, initiatorand seed growth monomer, as well as the choice of the type and amount ofammonium phosphate ester zwitterionic monomer, as well as other monomercomponents. Preferably the product latex has dispersed phase withaverage particle diameter of less than 1 μm, more preferably less than500 nm, most preferably in the range 100 to 400 nm. Preferably thepolydispersity of particle size (number average over weight averagediameter) is in the range 1.0 to 2.0.

It is preferred that the level of initiator for these low particle sizedistributions is in the range 0.001 to 0.5 weight % based on solids,preferably in the range 0.01 to 0.1 weight % . Preferably the ratio ofweight of combined seed monomer to seed growth polymer is in the range1:99 to 99:1, preferably in the range 1:50 to 1:10.

The seeded emulsion polymerization technique may be used to form acore-shell polymer product, using the techniques described above inconnection with the first aspect of the invention. In such a process theseed growth monomers comprise two or more mixtures including a coremixture and a shell mixture, usually differing in terms of composition.

The seeded emulsion polymerization process has preferred components asdescribed above in connection with the first aspect of the invention.

The polymer latex product of the first aspect of the invention forms afurther aspect of the invention. A novel stable latex comprises adispersion of polymer particles in aqueous continuous phase, having apolymer concentration in the range 20 to 60% by weight based on thetotal weight of the latex, an average particle diameter of less than 1μm, the polymer being formed from radical polymerised ethylenicallyunsaturated monomers comprising water-insoluble monomer and ammoniumphosphate ester zwitterionic monomer.

The novel latex may further comprise additional components. For instanceit may be desirable to add to the latex suspended particulate solidsselected from organic and inorganic water-insoluble materials.Particularly preferred are suspended inorganic solids such as pigments,preferably having particle sizes less than 1 μm. The latex mayadditionally comprise dissolved or miscible components for instance toimprove the storage stability of the latex, or to provide additionalproperties for the product of the final dried film. For instance, drugsmay be incorporated into the latex, either by adding a suspension or anaqueous or organic solvent-based solution to the latex. Colouring agentsmay also be included.

The novel latex, or the product of one of the novel polymerizationprocesses, may be used as a coating composition.

According to a further aspect of the invention there is provided a novelcoating process in which such a dispersion is coated onto a substrate toform a liquid coating on a surface thereof, and water is removed fromthe liquid coating to form a stable solid polymer coating on the saidsurface. Generally water is removed by evaporation although contact withprecipitating solvents may also be utilised. Evaporation may beconducted at raised temperature and/or reduced pressure, and coalescingacids, such as alcohols, esters, glycols or other ethers, may be used toprovide added control over film formation.

Preferably water removal is conducted under conditions of raisedtemperature under which the polymer particles coalesce to form acoherent and substantially void-free, preferably clear film.

The dried film may be subjected to additional steps such as curing, forinstance by heating, especially where the monomers include across-linking monomer such as monomers of the general formula IX above.Gamma or other e.m. radiation or ethyleneoxide treatment may also becarried out to cure and/or sterilise the film.

The product films have particularly desirable biocompatibilisingproperties. They are generally used in environments in which the coatedsurface is contacted with aqueous liquids, generally biological liquids,for instance containing dissolved protein or suspended cells, such asbacterial or, preferably, blood cells. Preferably such liquids areselected from blood and serum.

According to a further aspect of the invention there is provided a novelbiocompatibilising process in which a substrate is biocompatibilised bycoating it with a latex according to the third aspect of the inventionor which is the product of a process according to the first or secondaspects of the invention, water is removed, to leave a stable coating ofsolid polymer on the surface.

Some of the monomer compositions used in the first and second aspects ofthe invention are believed to be novel in themselves. Whilst the novelemulsion polymerization techniques are believed to optimise the polymerproperties, it is possible that other techniques may be suitable forcopolymerising these monomers to form polymers having desirablecharacteristics. Such novel polymers are obtainable by radicalpolymerization of ethylenically unsaturated monomers comprising:

i) 0.1 to 25% by weight of an ammonium phosphate ester zwitterionicmonomer;

ii) 0.1 to 25% by weight of a zwitterionic comonomer different to i);and

iii) 25 to 99% of a hydrophobic monomer.

Preferably this hydrophobic monomer is a compound as described above.Most preferably it is selected from the group consisting ofC₁₋₁₂-alkyl(alk)acrylates, C₂₋₁₂-alkyl- and -dialkyl-(alk)acrylamidesand styrene, and mixtures thereof.

The novel polymers may further comprise:

iv) 0.01 to 50% by weight hydrophilic monomer, preferably selected fromthe group consisting of C₁₋₄-hydroxyalkyl(meth)acrylates,C₁₋₄-hydroxyalkyl(meth)acrylamides,C₁₋₃-alkoxy-C₂₋₄-alkyl(meth)acrylates,C₁₋₃-alkoxy-C₂₋₄-alkyl(meth)acrylamides,C₁₋₃-alkoxy-oligoethoxy(meth)acrylates,C₁₋₄-dihydroxyalkyl(meth)acrylates, N-mono- or N,N- di- C₁₋₂ alkyl(meth)acrylamides, N-vinylactams, andC₂₋₄-hydroxyalkyl-oligoethoxy(meth)acrylates and mixtures thereof.

The hydrophilic monomer preferably comprises an oligoethoxylatedcompound, preferably in an amount in the range 0.1 to 10% by weightbased on the total weight of monomer. Preferably such a monomer isselected from C₁₋₃-alkoxy-oligoethoxy(meth)acrylates andC₂₋₄-hydroxyalkyl-oligoethoxy(meth)acrylates, more preferably the alkoxyterminated compounds.

In one embodiment the novel polymer comprises 0.01 to 20% by weight,more preferably 0.1 to 5% by weight reactive monomer, comprising thegeneral formula X defined above.

In another embodiment of the invention, the monomers include 0.01 to10%, preferably 0.1 to 2% by weight anionic monomer, preferably selectedfrom fumaric acid, maleic acid, vinyl sulphonic acid and styrenesulphonic acid, more preferably selected from acrylic and methacrylicacids, and is most preferably methacrylic acid.

In another embodiment of the polymer of the invention, the monomersinclude 1 to 25%, preferably 2 to 15% cationic monomer, preferably acompound of the general formula VIII defined above.

There is also provided in the present invention a film formed of thenovel polymer. Preferably the film is a coherent, substantially voidfree film, preferably in the form of a coating on a surface of asubstrate. The substrate is preferably the surface of a device for usein contact with biological fluids or organs, especially a device used incontact with aqueous liquids susceptible to fouling by proteins,carbohydrates, microbes or cells of higher organisms, cell culturesubstrates, assay devices, biosensors etc. Most preferably the substrateis the surface of a medical device, for instance an ophthalmic devicesuch as a contact lens, a corneal onlay or an ophthalmic implant, or isa coating on a prosthesis, a guidewire, a catheter, a drug deliveryimplant, a stent, a vascular graft, a blood filter or extra corporealcircuitry components

In a drug delivery device, the active drug may be incorporated into thefilm by being a component of the coating latex, or by contacting thecoated product, before or after curing, with a suitable drug to allowabsorption or adsorption in or to the film.

The following examples illustrate the invention:

EXAMPLE 1

The following components are used in a seeded emulsion polymerizationtechnique as described below:

TABLE 1 % (g) Reactor Charge Demin water 59.79 179.37 HEMA-PC 0.23 0.69Monomer Seed Methyl Methacrylate 0.44 1.32 Butyl Acrylate 0.44 1.32Initiator Seed Initiator 0.02 0.06 Demin water 2.66 7.98 Monomer Feed(Controlled pumping) Methyl methacrylate 7.3 21.9 Butyl acrylate 7.321.9 Trimethoxysilylpropyl methacrylate 0.77 2.31 Hydroxypropylmethacrylate 2.21 6.63 MethoxyPEG methacrylate (mwt 550) 1.31 3.93Methacrylic acid 0.11 0.33 Initiator Feed (Controlled pumping) Initiator0.07 0.21 Demin water 10.33 30.99 Dimethylammoniumpropyl sulphonate,ethyl 3.5 10.5 methacrylate Mop up Feed Demin water 2 6 Initiator 0.020.06 Alcohol addition Demin water 1 3 Benzyl alcohol 0.5 1.5 Total 100300

The reactor charge was first loaded into the reaction vessel. Theinternal reaction temperature was raised to 75° C. using a nitrogenpurge for 45 minutes. Once the temperature was reached and the 45minutes elapsed the nitrogen purge was switched to a blanket whilststirring at 250 to 300 rpm. The monomer seed was then added and thereaction held for 10 minutes. The initiator seed was then added and thereaction held for a further 10 minutes. The internal temperature wasthen raised to 85° C. over a period of 30 minutes allowing for any lightexotherms to occur. (These are usually in the order of 2-3° C.). Acolour change in the reactor charge ingredients was observed from a greyto a blue white colour indicating micelle formulation.

Once the 85° C. temperature had been reached the monomer and initiatorfeeds were fed simultaneously over 150 minutes at 85° C. When the feedsolutions had been added the reaction was held at 85° C. for a furtherhalf hour. The initiator mop-up feed was then added over one hour at 85°C. The reaction mix was then cooled to 40° C. and the alcohol added. Thereaction was held at 40° C. for a further 10 minutes. The polymer wasthen filtered through an 80 μm nylon mesh and then stored as adispersion.

The particle size dispersion was measured by Disk centrifugePhotosedimentometry (DCP). This technique is based on Stokes Law. Thenumber average diameter was 107 nm with a standard deviation of 31 nmand the weight average diameter was 181 nm with a standard deviation of86 nm.

The product was analysed to determine the levels of residual monomer.The results are shown in Table 2 below.

TABLE 2 Residual Monomer Monomer ppm methylmethacrylate <30butylacrylate <30 methacrylic acid  <5 hydroxypropylmethacrylate <25silyl monomer  <5 sulphobetaine monomer <1800  MPC  <5

EXAMPLE 2—COATING PROCESS

The product of Example 1 was diluted with demineralised water to aconcentration of 10 g/l (solids). The coating process, in each case,involved cleaning the substrates with dichloromethane then somicatingthe substrates in ethanol for two minutes. The cleaned substrates werethen coated with the diluted product latex, allowed to dry for fiveminuted at room temperature, then placed in an oven at 70° C. for fourhours to cure and cross-link the film.

The coated substrates were subjected to various tests forbiocompatibility.

2.1 Fibrinogen Adhesion

In the first test the extent of fibrinogen adhesion to the substrate istested using the protocol substantially as described in WO-A-9301221.The control, uncoated substrates were also tested and the levels ofreduction are shown in Table 3.

TABLE 3 Fibrinogen Reduction (Fg) on Various Substrates Uncoated CoatedSubstrate Mean Absorbance @ 450 nm (S.D) Glass 1.772 (0.200) 0.807(0.074) Steel 1.756 (0.223) 0.382 (0.053) PVC 1.283 (0.227) 0.461(0.119) PET 1.472 (0.164) 0.499 (0.067)

2.2 E. coli Adhesion

The adhesion of E. coil to the substrates was tested using the followingtechnique: The samples were incubated with E. coli in a nutrient broth(Oxoid) for 4 or 18 hours at 37° C. The samples were washed in phosphatebuffered saline and incubated with a 1% solution of bovine serum albuminin phosphate buffered saline for 1 hour. This treatment is intended toblock surface portions not coated with E. coli to prevent non-specificattachment of the reagent in the next step of the process. After washingin phosphate buffered saline, the sample were incubated with rabbit E.coli polyclonal antibody conjugated to horseradish peroxidase (1/200)for 1 hour, washed for 10 minutes in phosphate buffered saline andincubated with a chromogenic substrate OPD (orthophenylene diamine)substrate buffer for a predetermined period in the range 10-20 minutes.The absorbance was read at 450 nm. This enzyme linked immunoassay resultis recognised to correlate to the level of adhesion of E. coli cells.

The results are shown in Table 4.

TABLE 4 E-Coli Reduction on Various Substrates Uncoated Coated SubstrateMean Absorbance @ 450 nm (S.D) Glass 1.850 (0.173) 0.381 (0.091) Steel0.439 (0.095) 0.184 (0.032) PVC 0.867 (0.237) 0.173 (0.091) PET 0.634(0.282) 0.255 (0.016)

The results show that, on all four substrates, the polymers of theinvention confer desirable biocompatibility as illustrated by thefibrinogen adsorption and E. coli adhesion tests.

2.3 Blood Cell Adhesion to Blood Filter Material

In a further performance test, the latex was used to coat a blood filterformed of polyethylene terephthate (PET). The coated filter wascontacted with whole blood and observed as described in WO-A-9301221.The product was observed under scanning electron microscope. Whilst thecoated product may be seen to contaminated by high levels of depositedmaterial, the coated filter appears to have no adhered materials.

EXAMPLE 3—OTHER POLYMERS

The emulsion polymerization process described in Example 1 was repeatedbut omitting one or more of the ammonium phosphate ester zwitterionicmonomer, betaine comonomer and PEG monomer. The various latexes wereanalysed to determine the number average particle size and weightaverage particle size using the above techniques.

It was found that the omission of the sulphobetaine monomer reduced thestability of the emulsion, resulting in some build up of coagulum. Thenumber average molecular weight following filtration of the latexproduct was determined to be 133 nm (standard deviation 41 nm), whilstthe weight average values were 186 (78) nm.

For the polymer in which the PEG was omitted, the particle size of thelatex remained low and with a low spread (number average particle size100(21) nm, weight average 119 (33) nm), but the coated polymer hadreduced wettability as judged by determining the critical wettingsurface tension on the filter of the type used in Example 2.

Where ammonium phosphate ester zwitterionic monomer was omitted, therewas a significant reduction in latex stability with a build up ofcoagulum. The number average particle size was measured at 151(51) nmwith the weight average being 227 (96) nm.

Omitting both zwitterionic monomers resulted in poor particle sizecontrol as well as higher particle sizes and a bimodal distribution ofparticle sizes. The number average particle size was 394(73) nm with theweight average being 433(75) nm.

Omitting both PEG based monomer and ammonium phosphate ester zwitterionagain resulted in inadequate latex stability with a build up ofcoagulum. The measured particle sizes were number average 160(43) nm andweight average 210 (98) nm. This product also had poor critical wettingsurface tension for the coated filter.

Where both betaine monomer and PEG based monomer were omitted,inadequate latex stability was achieved with a build up of coagulum. Theparticle sizes were greatly increased as compared to the polymer ofExample 1, with number average being 510(55) nm and the weight averagebeing 531(69) nm.

Omitting both zwitterionic monomers and the PEG monomer resulted in avery poor emulsion, with very high particle sizes and particle sizespreads. The number average particle size was 754(211) nm with theweight average being 1012 (382) nm.

EXAMPLE 4—POLYMER WITH CATIONIC COMONOMER

The monomer composition and polymerization process described above forExample 1 was adapted to incorporate 5 or 10% by weight cationic monomeras part of the mainfeed, retaining the same relative concentrations ofthe remaining monomers and same overall total solids content.

The latex product was coated using the general technique desribed inExample 2 onto the filters used in Example 2.3 and tested for theircritical wetting surface tension. The results show that the CWST for the5% cationic polymer was raised to 65 dyne/cm, as compared to 55 for thefilter coated according to Example 2 and 45 dyne/cm for the uncoatedfilter.

A glass coverslip coated using the same general technique as in Example2 was analysed by atomic force microscope for coating smoothness,thickness and the removal force. The average coating smoothness was 6.5nm as compared to 4.0 nm for the uncoated glass. The thickness was inthe range 30 to 150 nm. The removal force was 2.850 μN.

EXAMPLE 5—CORE-SHELL LATEX PREPARATION

The reactor was loaded with 129 g of distilled water and 0.69 g of MPC,following which the temperature was raised to 75° C. with nitrogen purgeand stirring at 270 rpm. The monomer seed was added (1.32 g methylmethacrylate and 1.32 g butyl acrylate) and after 5 minutes theinitiator seed was added (0.06 g ammonium persulfate (APS) in 8 gwater). The reaction temperature was raised to 85° C. for 30 minutesafter which the core monomer feed was added (15.12 g methylmethacrylate, 3.78 g butyl acrylate, 0.6 g ethylene glycoldimethacrylate and 0.6 g methoxy-polyethylene glycol methacrylate (550Mw)) together with another initiator feed (0.21 g APS, 10.5 g MPC in 31g water). Monomer was added over approximately an hour and immediatelyfollowed by a shell feed (12.8 g methyl methacrylate, 12.8 g butylacrylate, 2.3 g trimethoxysilyl propyl methacrylate, 6.6 ghydroxypropylmethacrylate and 3.0 g of methoxy-polyethylene glycolmethacrylate (550 Mw) and 0.3 g methacrylic acid). This was held at 85°C. for a further hour before addition of an initiator spike (0.06 g APSin 6.0 g water) and a further 30 minutes reaction time before beingcooled. The solution was filtered through glass wool to remove a smallamount of coagulum from the stirrer. 1.5 g benzyl alcohol was added in3.0 g water as preservative.

The latex was cast onto a glass plate to form a tough film that wascured to an insoluble film upon heating at 70° C. in an oven.

Particle analysis of the milky white liquid showed the followingcharacteristics of the latex:

Helium pycnometry for average density 1.1755 cm³ ± 0.0019 (1) (n = 3):1.1727 cm³ ± 0.0136 (2) 1.1707 cm³ ± 0.0099 (3) Disk centrifugationphotosedimentometry for 0.1610 ± 0.045 μm (1) weight average (n = 2):0.1600 ± 0.049 μm (2) Polydispersity (n = 2): 1.238 (1) 1.280 (2)

What is claimed is:
 1. An emulsion polymerization process comprising thefollowing steps: a) providing a mixture of ethylenically unsaturatedmonomers including water insoluble monomer; b) dispersing the mixture ofethylenically unsaturated monomers into an aqueous liquid to form anoil-in-water emulsion; c) adding to the oil-in-water emulsion anammonium phosphate ester zwitterionic monomer; d) adding a water-solubleradical initiator to the oil-in water emulsion; e) polymerizing themonomers to form a product latex of polymer having a polymer solidsconcentration in the product of at least 20% by weight.
 2. An emulsionpolymerization process according to claim 1 in which the solidsconcentration of the product is up to 60%.
 3. An emulsion polymerizationprocess according to claim 2 in which the solids concentration of theproduct is in the range 25 to 50%.
 4. An emulsion polymerization processaccording to claim 1 in which the oil-in-water emulsion is substantiallyfree of non-polymerisable surfactants.
 5. An emulsion polymerizationprocess according to claim 1 in which the ammonium phosphate esterzwitterionic monomer is included in the process in an amount in therange 0.01 to 5% by weight based on the total weight of monomers.
 6. Anemulsion polymerization process according to claim 5 in which the saidamount is in the range 0.05 to 2% by weight.
 7. An emulsionpolymerization process according to any preceding claim in which theammonium phosphate ester zwitterionic monomer has the general formula IYBX  I in which X is said ammonium phosphate ester zwitterionic group; Bis selected from the group consisting of a bond, and straight andbranched alkanediyl, alkylene oxaalkylene, and alkylene(oligooxalkylene) groups, optionally containing one or more fluorinesubstituents; and Y is an ethylenically unsaturated group selected fromthe group consisting of H₂C═CR—CO—A—, H₂C═CR—C₆H₄—A¹—, H₂C═CR—CH₂A²—,R²O—CO—CR═CR—CO—O—, RCH═CH—CO—O—, RCH═C(COOR²)CH₂—CO—O—,

A is —O— or NR¹; A¹ is selected from the group consisting of a bond,(CH₂)_(n)A² and (CH₂)_(n)SO₃— in which n is 1 to 12; A² is selected fromthe group consisting of a bond, —O—, O—CO—, —CO—O, —CO—NR¹—, —NR¹—CO,—O—CO—NR¹—, and —NR¹—CO—O—; R is hydrogen or C₁₋₄ alkyl; R¹ is selectedfrom the group consisting of hydrogen, C₁₋₄ alkyl and BX; and R² ishydrogen or C₁₋₄ alkyl.
 8. An emulsion polymerization process accordingto claim 1 in which the monomers include at least 50% by weight based ontotal ethyleneically unsaturated monomers of a hydrophobic ethylenicallyunsaturated polymerisable compound.
 9. An emulsion polymerizationprocess according to claim 8 in which the said hydrophobic compound isselected from the group consisting of C₁₋₁₂ alkyl(alk)acrylates andC₂₋₁₂-alkyl and -dialkyl(alk)acrylamides, styrene, and mixtures thereof.10. An emulsion polymerization process according to claim 1 comprisingfurther adding to the oil-in-water emulsion a sulpho- or carboxy-betainemonomer.
 11. An emulsion polymerization process according to claim 10 inwhich the weight ratio of betaine monomer to ammonium phosphate esterzwitterionic monomer is in the range (1-50):1.
 12. An emulsionpolymerization process according to claim 11 in which the said ratio isin the range (5-20):1.
 13. An emulsion polymerization process accordingto claim 1 comprising adding to the oil-in-water emulsion a hydrophilicmonomer.
 14. An emulsion polymerization process according to claim 13 inwhich the ydrophilic monomer is selected from the group consisting ofC₂₋₄-hydroxyalkyl(meth)acrylates, C₁₋₄-hydroxyalkyl(meth)acrylamides,C₁₋₃-alkoxy-C₂₋₄-alkyl(meth)acrylates,C₁₋₃-alkoxy-C₂₋₄-alkyl(meth)acrylamides,C₁₋₃-alkoxy-oligoethoxy(meth)acrylatesC₁₋₄-dihydroxyalkyl(meth)acrylates, N-mono- and N,N- di- C₁₋₂ alkyl(meth)acrylamides, N-vinylactams and C₂₋₄ hydroxyalkyloligoethoxy(meth)acrylates, and mixtures thereof.
 15. An emulsionpolymerization process according to claim 13 in which the saidhydrophilic monomer is added in an amount in the range 0.1 to 50% byweight, based on the total weight of monomer.
 16. A process according toclaim 15 in which the said range is 5 to 20% by weight.
 17. An emulsionpolymerization process according to claim 1 comprising adding to theoil-in-water emulsion an acidic monomer in an amount to confer an acidicpH on the oil-in-water emulsion.
 18. An emulsion polymerization processaccording to claim 17 in which the acidic monomer is acylic acid ormethacrylic acid, and it is present in an amount in the range 0.1 to 5%by weight based on the total weight of monomers.
 19. An emulsionpolymerization process according to claim 1 comprising adding to theoil-in-water emulsion a cationic monomer, of the general formula VIIIY²B²Q  VIII in which Y² is an ethylenically unsaturated group selectedfrom the group consisting of H₂C═CR¹⁹—CO—A⁸—, H₂C═CR¹⁹—C₆H₄—A⁹—,H₂C═CR¹⁹—CH₂A¹⁰, R²¹O—CO—CR¹⁹═CR¹⁹—CO—O—, R¹⁹CH═CH—CO—O—,R¹⁹CH═C(COOR²¹)CH₂—CO—O—,

A⁸ is —O— or —NR²⁰—; A⁹ is selected from the group consisting of a bond,(CH₂)_(q)A¹⁰ and (CH₂)_(q)SO₃— in which q is 1 to 12; A¹⁰ is selectedfrom the group consisting of a bond, —O—, O—CO—, —CO—O, —CO—NR²⁰—,—NR²⁰—CO, O—CO—NR²⁰—, and NR²⁰—CO—O—; R¹⁹ is hydrogen or C₁₋₄ alkyl; R²⁰is selected from the group consisting of hydrogen, C₁₋₄-alkyl and BX;R²¹ is hydrogen or C₁₋₄ alkyl; B² is selected from the group consistingof a bond, and straight and branched alkanediyl, alkylene oxaalkylene,and alkylene (oligooxalkylene) group, optionally containing one or morefluorine substituents; and Q is selected from the group consisting of—N^(⊕)R²² ³, —P^(⊕)R²³ ₃ and —S^(⊕)R²³ ₂ ₂ in which the groups R²² arethe same or different and each is selected from the group consisting ofhydrogen, alkyl of 1 to 6 carbon atoms, C₁₋₆ hydroxyalkyl, aryl, andC₇₋₁₂ aralkyl, or two of the groups R²² together with the nitrogen atomto which they are attached form an aliphatic heterocyclic ringcontaining from 5 to 7 atoms, or the three groups R²² together with thenitrogen atom to which they are attached form a fused ring structurecontaining from 5 to 7 atoms in each ring, and optionally one or more ofthe groups R²² is substituted by a hydrophilic functional group, and thegroups R²³ are the same or different and each is R²² or a group OR²²,where R²² is as defined above mutatis mutandis.
 20. An emulsionpolymerization process according to claim 19 in which Y² isH₂C═CR¹⁹COA—, in which R¹² is hydrogen or methyl and A is —O— or —NH—,B² is straight chain C₂₋₆ alkanediyl group and Q is —N^(⊕)R³³ ₃ whereeach R²² group is a C₁₋₄ alkyl group.
 21. An emulsion polymerizationprocess according to claim 1 comprising further adding to theoil-in-water emulsion a reactive monomer having the general formula IXY³B³Q¹  IX in which Y³ is an ethylenically unsaturated group selectedfrom the group consisting of H₂C═CR²⁴—CO—A¹¹—, H₂C═CR²⁴—C₆H₄—A¹²—,H₂C═CR¹⁹—CH₂A¹³, R²⁶O—CO—CR²⁴═CR—CO—O—, R²⁴CH═CH—CO—O—,R²⁴CH═C(COOR²⁶)CH₂—CO—O—,

A¹¹ is —O— or —NR²⁵; A¹² is selected from the group consisting of abond, (CH₂)_(r)A¹³ and (CH₂)_(r)SO₃— in which r is 1 to 12; A¹³ isselected from the group consisting of a bond, —O—, O—CO—, CO—O,—CO—NR²⁵—, —NR²⁵—CO, —O—CO—NR²⁵—, and NR²⁵—CO—O—; R²⁴ is hydrogen orC₁₋₄ alkyl; R²⁵ is selected from the group consisting of hydrogen, C₁₋₄₋alkyl and B³Q¹. R²⁶ is hydrogen or C₁₋₄ alkyl; B³ is selected from thegroup consisting of a bond, straight and branched alkanediyl, alkyleneoxaalkylene, and alkylene (oligooxalkylene) groups, optionallycontaining one or more fluorine substituents. Q¹ is a reactive groupselected from the group consisting of aldehyde groups; silane andsiloxane groups containing one or more substituents selected fromhalogen atoms and C₁₋₄-alkoxy groups; hydroxyl; amino; carboxyl; epoxy;—CHOHCH₂Hal (in which Hal is selected from chlorine, bromine and iodineatoms); succinimido; tosylate; triflate; imidazole carbonyl amino;optionally substituted triazine groups; cinnamyl; ethylenically andacetylenically unsaturated groups; acetoacetoxy; methylol; andchloroalkylsulphone groups; acetoxy; mesylate; carbonyl di(cycloalkylcarbodiimidoyl; and oximino.
 22. An emulsion polymerization processaccording to claim 21 in which Y³ is H₂C═CR²⁴COA″— in which R²⁴ ishydrogen or methyl and A″ is —O— or NH—, B³ is a straight chainC₂₋₆-alkanediyl group; and Q¹ is a trimethoxysilyl group.
 23. Anemulsion polymerization process according to claim 22 in which themonomers include a hydrophilic monomer selected from the groupconsisting of C₂₋₄ hydroxyalkyl(alk)acrylates and mono- or di- C₂₋₄hydroxyalkyl(alk)acrylamides.
 24. An emulsion polymerization processcomprising the following steps: i) adding an ethylenically unsaturatedammonium phosphate ester zwitterionic monomer and a water-solubleradical initiator in a first stage to an aqueous liquid to form anaqueous continuous phase; ii) forming a monomer seed mixture comprisingwater-insoluble ethylenically unsaturated monomer, and water-solubleethylenically unsaturated monomer; iii) before, simultaneously or afterstep i) adding the monomer seed mixture to the aqueous continuous phaseto form a water-in-oil emulsion; iv) after both steps i) and iii) addingwater-soluble initiator and initiating polymerization to form anoil-in-water dispersion of emulsion-polymerised polymer seeds; v)forming a seed growth monomer mixture comprising water-insolubleethylenically unsaturated monomer; vi) dispersing the seed growthmonomer to the dispersion of emulsion-polymerised seeds to form anoil-in-water seed growth emulsion; vii) adding seed growth initiator tothe seed growth emulsion and initiating seed growth polymerization inthe seed growth emulsion to form a product latex.
 25. An emulsionpolymerization process according to claim 24 in which the composition ofthe combination of monomer seed mixture and zwitterionic monomer isdifferent to the composition of the seed growth monomer mixture.
 26. Anemulsion polymerization process according to claim 25 in which themonomer seed mixture consists substantially only of hydrophobicethylenically unsaturated monomer.
 27. An emulsion polymerizationprocess according to claim 26 in which the hydrophobic monomer isselected from the group consisting of C₁₋₁₂ alkyl(alk)acrylates andC₂₋₁₂-alkyl and di-alkyl(ak)acrylamides, styrene, and mixtures thereof.28. An emulsion polymerization process according to claim 25 in whichthe seed growth monomer mixture comprises ethylenically unsaturatedammonium phosphate ester zwitterionic monomer.
 29. An emulsionpolymerization process according to claim 28 in which seed growthmonomer mixture comprises water-soluble ethylenically unsaturatedmonomers.
 30. An emulsion polymerization process according to claim 29in which the said water-soluble monomers comprise a hydrophilic monomer.31. A process according to claim 29 in which the said water solublemonomers include acrylic or methacrylic acid.
 32. An emulsionpolymerization process according to claim 29 in which the saidwater-soluble monomers include a cationic monomer, of the generalformula VIII Y² B² Q  VIII in which Y² is an ethylenically unsaturatedgroup selected from the group consisting of H₂C═CR¹⁹—CO—A⁸—,H₂C═CR¹⁹—C₆H₄—A⁹—, H₂C═CR¹⁹—CH₂A¹⁰, R²¹O—CO—CR¹⁹═CR¹⁹—CO—O—,R¹⁹CH═CH—CO—O—, R¹⁹CH═C(COOR²¹)CH₂—CO—O—,

A⁸ is —O— or —NR²⁰—; A⁹ is selected from the group consisting of a bond,(CH₂)_(q)A¹⁰ and (CH₂)_(q)SO₃— in which q is 1 to 12; A¹⁰ is selectedfrom the group consisting of a bond, —O—, O—CO—, —CO—O, —CO—NR²⁰—,—NR²⁰—CO, O—CO—NR²⁰—, and NR²⁰—CO—O—; R¹⁹ is hydrogen or C₁₋₄ alkyl; R²⁰is selected from the group consisting of hydrogen, C₁₋₄₋ alkyl and BX;R²¹ is hydrogen or C₁₋₄ alkyl; B² is selected from the group consistingof a bond, and straight and branched alkanediyl, alkylene oxaalkylene,and alkylene (oligooxalkylene) group, optionally containing one or morefluorine substituents; and Q is selected from the group consisting of—N^(⊕)R₃ ²²,—P^(⊕)R²³ ₃ and —S^(⊕)R²³ in which the groups R²² are thesame or different and each is selected from the group consisting ofhydrogen, alkyl of 1 to 6 carbon atoms, C₁₋₆ hydroxyalkyl, aryl, andC₇₋₁₂ aralkyl, or two of the groups R²² together with the nitrogen atomto which they are attached form an aliphatic heterocyclic ringcontaining from 5 to 7 atoms, or the three groups R²² together with thenitrogen atom to which they are attached form a fused ring structurecontaining from 5 to 7 atoms in each ring, and optionally one or more ofthe groups R²² is substituted by a hydrophilic functional group, and thegroups R²³ are the same or different and each is R²² or a group OR²²,where R²² is as defined above mutatis mutandis.
 33. An emulsionpolymerization process according to claim 32 in which Y² isH₂C═CR¹⁹COA—, in which R¹² is hydrogen or methyl and A is —O— or —NH—,B² is straight chain C₂₋₆ alkanediyl gruop and Q is —N^(⊕)R₃ ²² whereeach R²² group is a C₁₋₄ alkyl group.
 34. An emulsion polymerizationprocess according to claim 24 in which at least a portion of seed growthmonomers are premixed before being added to the continuous phase in stepiv.
 35. An emulsion polymerization process according to claim 34 inwhich the seed growth monomer mixture is continuously fed into theoil-in-water dispersion compositions of emulsion-polymerised seeds overa monomer feed period during which polymerization continues.
 36. Anemulsion polymerization process according to claim 35 comprisingproviding an initiator feed comprising the seed growth initiator andcontinuously feeding the initiator feed, into the oil-in-waterdispersion comprising emulsion polymerised seeds throughout the monomerfeed period.
 37. An emulsion polymerization process according to claim35 in which a portion of initiator feed is added to the polymerisedgrowth polymerization mixture after all the premixed seed growth monomermixture has been added under conditions such that radicals are formedfrom the initiator.
 38. An emulsion polymerization process according toclaim 36 in which the initiator feed comprises water-soluble monomer.39. An emulsion polymerization process according to claim 38 in whichthe water-soluble monomer comprises a sulpho- or carboxy-betainemonomer.
 40. An emulsion polymerization process according to claim 24 inwhich the latex product comprises a stable dispersion of polymerparticles, having a polymer concentration in the range 20 to 60% byweight.
 41. An emulsion polymerization process according to claim 24 inwhich the latex product comprises a dispersed phase having a particlediameter less then 1 μm.
 42. An emulsion polymerization according toclaim 41 in which the particle diameter is in the range 100 to 400 μm.